Zeptomole Imaging of Cytosolic MicroRNA Cancer Biomarkers with A Light-Controlled Nanoantenna
Corresponding Author: Yuehe Lin
Nano-Micro Letters,
Vol. 13 (2021), Article Number: 213
Abstract
Detecting and quantifying intracellular microRNAs (miRNAs) are a critical step in resolving a cancer diagnostic and resolving the ensemble of gene products that orchestrate the living state of cells. However, the nanoprobe for detecting low abundance miRNAs in cell cytosol is restricted by either the “one-to-one” signal-trigger model or difficulty for cytosol delivery. To address these challenges, we designed a light-harvesting nanoantenna-based nanoprobe, which directs excitation energy to a single molecule to sensitively detect cytosolic miRNA. With light irradiation, the light-harvesting nanoantenna effectively disrupted lysosomal structures by generation of reactive oxygen species, substantially achieved cytosol delivery. The nanoantenna containing > 4000 donor dyes can efficiently transfer excitation energy to one or two acceptors with 99% efficiency, leading to unprecedented signal amplification and biosensing sensitivity. The designed nanoantenna can quantify cytosolic miR-210 at zeptomolar level. The fluorescence lifetime of the donor exhibited good relationship with miR-210 concentration in the range of 0.032 to 2.97 amol/ngRNA. The zeptomole sensitivity of nanoantenna provides accurate bioimaging of miR-210 both in multiple cell lines and in vivo assay, which creates a pathway for the creation of miRNA toolbox for quantitative epigenetics and personalized medicine.
Highlights:
1 Based on førster resonance energy transfer, the nanoantenna containing over 4000 donor dyes can achieve unprecedented signal amplification and biosensing sensitivity.
2 With light irradiation, the light-harvesting nanoantenna effectively disrupted lysosomal structures by generation of reactive oxygen species, substantially achieved cytosol delivery.
3 The zeptomolar sensitivity of nanoantenna provides accurate bioimaging of miR-210 in multiple cell lines and in vivo assay, which creates a pathway for the creation of miRNA toolbox for quantitative epigenetics and personalized medicine.
Keywords
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- H. Dong, X. Meng, W. Dai, Y. Cao, H. Lu et al., Highly sensitive and selective microRNA detection based on DNA-bio-bar-code and enzyme-assisted strand cycle exponential signal amplification. Anal. Chem. 87, 4334–4340 (2015). https://doi.org/10.1021/acs.analchem.5b00029
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- Y. Huang, J. Xing, Q. Gong, L.C. Chen, G. Liu et al., Reducing aggregation caused quenching effect through co-assembly of PAH chromophores and molecular barriers. Nat. Commun. 10, 169 (2019). https://doi.org/10.1038/s41467-018-08092-y
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J. Li, J. Wang, S. Liu, N. Xie, K. Quan et al., Amplified FRET nanoflares: an endogenous mrna-powered nanomachine for intracellular microRNA imaging. Angew. Chem. Int. Ed. 59, 20104–20111 (2020). https://doi.org/10.1002/anie.202008245
H. Peng, X.F. Li, H. Zhang, X.C. Le, A microRNA-initiated DNAzyme motor operating in living cells. Nat. Commun. 8, 14378 (2017). https://doi.org/10.1038/ncomms14378
X. Zhang, Y. Xiao, X. Qian, A ratiometric fluorescent probe based on FRET for imaging Hg2+ ions in living cells. Angew. Chem. Int. Ed. 47, 8025–8029 (2008). https://doi.org/10.1016/j.snb.2016.09.177
X. Li, X. Gao, W. Shi, H. Ma, Design strategies for water-soluble small molecular chromogenic and fluorogenic probes. Chem. Rev. 114, 590–659 (2014). https://doi.org/10.1021/cr300508p
J. Chan, S.C. Dodani, C.J. Chang, Reaction-based small-molecule fluorescent probes for chemoselective bioimaging. Nat. Chem. 4, 973–984 (2012). https://doi.org/10.1038/nchem.1500
S. Egloff, N. Melnychuk, A. Reisch, S. Martin, A.S. Klymchenko, Enzyme-free amplified detection of cellular microRNA by light-harvesting fluorescent nanoparticle probes. Biosens. Bioelectron. 179, 113084 (2021). https://doi.org/10.1016/j.bios.2021.113084
C. Chen, D.A. Ridzon, A.J. Broomer, Z. Zhou, D.H. Lee et al., Real-time quantification of microRNAs by stem-loop RT-PCR. Nucl. Acids Res. 33, e179 (2005). https://doi.org/10.1093/nar/gni178
R.W. Carthew, E.J. Sontheimer, Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642–655 (2009). https://doi.org/10.1016/j.cell.2009.01.035
L. Nuhn, S. Van Herck, A. Best, K. Deswarte, M. Kokkinopoulou et al., FRET monitoring of intracellular ketal hydrolysis in synthetic nanoparticles. Angew. Chem. Int. Ed. 57, 10760–10764 (2018). https://doi.org/10.1002/anie.201803847
Y. Liu, G. Yang, S. Jin, R. Zhang, P. Chen et al., J-Aggregate-based FRET monitoring of drug release from polymer nanoparticles with high drug loading. Angew. Chem. Int. Ed. 59, 20065–20074 (2020). https://doi.org/10.1002/anie.202008018
B. Rathore, K. Sunwoo, P. Jangili, J. Kim, J.H. Kim et al., Nanomaterial designing strategies related to cell lysosome and their biomedical applications: a review. Biomaterials 211, 25–47 (2019). https://doi.org/10.1016/j.biomaterials.2019.05.002
J. Chen, J. Li, J. Zhou, Z. Lin, F. Cavalieri et al., Metal-phenolic coatings as a platform to trigger endosomal escape of nanoparticles. ACS Nano 13, 11653–11664 (2019). https://doi.org/10.1021/acsnano.9b05521
P.K. Selbo, A. Weyergang, A. Høgset, O.J. Norum, M.B. Berstad et al., Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. J. Controll. Release 148, 2–12 (2010). https://doi.org/10.1016/j.jconrel.2010.06.008
K. Berg, M. Folini, L. Prasmickaite, P.K. Selbo, A. Bonsted et al., Photochemical internalization: a new tool for drug delivery. Curr. Pharm. Biotechnol. 8, 362–372 (2007). https://doi.org/10.2174/138920107783018354
A. Qu, M. Sun, L. Xu, C. Hao, X. Wu et al., Quantitative zeptomolar imaging of miRNA cancer markers with nanoparticle assemblies. Proc. Natl. Acad. Sci. USA 116, 3391–3400 (2019). https://doi.org/10.1073/pnas.1810764116
L. Ji, Y. Sang, G. Ouyang, D. Yang, P. Duan et al., Cooperative chirality and sequential energy transfer in a supramolecular light-harvesting nanotube. Angew. Chem. Int. Ed. 58, 844–848 (2019). https://doi.org/10.1002/anie.201812642
P.Z. Chen, Y.X. Weng, L.Y. Niu, Y.Z. Chen, L.Z. Wu et al., Light-harvesting systems based on organic nanocrystals to mimic chlorosomes. Angew. Chem. Int. Ed. 55, 2759–2763 (2016). https://doi.org/10.1002/anie.201510503
X.M. Chen, Q. Cao, H.K. Bisoyi, M. Wang, H. Yang et al., An efficient near-infrared emissive artificial supramolecular light-harvesting system for imaging in the golgi apparatus. Angew. Chem. Int. Ed. 59, 10493–10497 (2020). https://doi.org/10.1002/anie.202003427
Z. Wu, M. Liu, Z. Liu, Y. Tian, Real-time imaging and simultaneous quantification of mitochondrial h2o2 and atp in neurons with a single two-photon fluorescence-lifetime-based probe. J. Am. Chem. Soc. 142, 7532–7541 (2020). https://doi.org/10.1021/jacs.0c00771
L. Ge, Y. Tian, Fluorescence lifetime imaging of p-tau protein in single neuron with a highly selective fluorescent probe. Anal. Chem. 91, 3294–3301 (2019). https://doi.org/10.1021/acs.analchem.8b03992
K. Zhou, H.K. Bisoyi, J.Q. Jin, C.L. Yuan, Z. Liu et al., Light-driven reversible transformation between self-organized simple cubic lattice and helical superstructure enabled by a molecular switch functionalized nanocage. Adv. Mater. 30, e1800237 (2018). https://doi.org/10.1002/adma.201800237
Y.X. Zhu, H.R. Jia, G.Y. Pan, N.W. Ulrich, Z. Chen et al., Development of a light-controlled nanoplatform for direct nuclear delivery of molecular and nanoscale materials. J. Am. Chem. Soc. 140, 4062–4070 (2018). https://doi.org/10.1021/jacs.7b13672
K.Y. Pu, K. Li, B. Liu, Cationic oligofluorene-substituted polyhedral oligomeric silsesquioxane as light-harvesting unimolecular nanoparticle for fluorescence amplification in cellular imaging. Adv. Mater. 22, 643–646 (2010). https://doi.org/10.1002/adma.200902409
Y. Huang, J. Xing, Q. Gong, L.C. Chen, G. Liu et al., Reducing aggregation caused quenching effect through co-assembly of PAH chromophores and molecular barriers. Nat. Commun. 10, 169 (2019). https://doi.org/10.1038/s41467-018-08092-y
M.H. Moros, B. Garet, E. Dias, J.T. Sáez, B. Grazú et al., Monosaccharides versus PEG functionalized NPs: influence in the cellular uptake. ACS Nano 6, 1565–1577 (2012). https://doi.org/10.1021/nn204543c
N. Cheng, Y. Song, Q.Q. Fu, D. Du, Y.B. Luo et al., Aptasensor based on fluorophore-quencher nano-pair and smartphone spectrum reader for on-site quantification of multi-pesticides. Biosens. Bioelectron. 117, 75–83 (2018). https://doi.org/10.1016/j.bios.2018.06.002
X. Huang, L. Ding, K.L. Bennewith, R.T. Tong, S.M. Welford et al., Hypoxia-inducible MIR-210 regulates normoxic gene expression involved in tumor initiation. Mol. Cell 35, 856–867 (2009). https://doi.org/10.1016/j.molcel.2009.09.006